Insect control process with synthetic hormones

ABSTRACT

Methylenedioxybenzyloxy and methylenedioxyphenoxy ethers of straight chain terpenoid compounds and their epoxides were synthesized and found to mimic the juvenile hormones of insects and be extremely effective control agents.

United States Patent [191 Bowers [54] INSECT CONTROL PROCESS WITH SYNTHETIC HORMONES [75] Inventor: William S. Bowers, Bowie, Md.

[73] Assignee: The United States of America as represented by the Secretary of Agriculture [52] US. Cl ..424/282, 424/D1G. 12 [51] Int. Cl. ..A0ln 9/28 [58] Field of Search ..424/DIG. 12, 282

[451 Apr. 3, 1973 [56] References Cited UNlTED STATES PATENTS 3,453,362 7/1969 Cruickshank ..260/240 3,513,176 5/1970 Andrews et al ..260/348 Primary ExaminerAlbert T. Meyers Assistant Examiner-Vincent D. Turner Att0rneyR. Hoffman et a1.

[57] ABSTRACT Methylenedioxybenzyloxy and methylenedioxyphenoxy ethers of straight chain terpenoid compounds and their epoxides were synthesized and found to mimic the juvenile hormones of insects and be extremely effective control agents.

29 Claims, No Drawings INSECT CONTROL PROCESS WITH SYNTHETIC HORMONES This application is a division of Ser. No. 788,651, filed Jan. 2, 1969, now US. Pat. No. 3,563,982.

A non-exclusive, irrevocable, royalty-free license in the invention herein described, throughout the world for all purposes of the US. Government, with the power to grant sublicenses for such purposes, is hereby granted to the Government of the United States of America.

This invention relates to insect control and more particularly to compounds and to the preparation of compounds that have high juvenile and gonadotropic hormone activity and that are effective in breaking diapause in insects.

Diapause is a condition of physiological arrest during which there is little or no activity, feeding, mating or egg laying. Diapause is utilized by insects as a defense mechanism to allow them to survive winter, summer, drought, and other period of extreme environmental stress. If diapause is prevented or broken artificially the insect is unable to survive.

it has been shown that diapause can be broken in several adult insects by treatment with the 10,1 1 epoxide of methyl farnesenate, the preparation of which is described in patent application Ser. No. 597,484, filed Nov. 28, 1966, now abandoned. However, the new compounds of the present invention are much more effective at breaking diapause since they are to 100 times more active than the esters of 10,] l epoxy farnesenic acid and are therefore of tremendous economic importance.

There is considerable concern throughout the world about the persistence of many insecticides and insectide residues in our environment and the potential hazard that these materials represent to human populations. in addition, many species of insect pests have become resistant or immune to many of the insecticides on the market. Thus, more selective chemicals are required which will not pose a threat to human populations and to which the insects will not be able to develop resistance.

The compounds of the present invention should be suitable replacements for the insecticides now being used to control stored product insects and many social pests such as fireants and termites. In addition, it may be feasible to use these compounds in field applications to control a wide variety of insects, the toxicity of the compounds to vertebrates should be insignificant and the cost to produce them commercially should be very competitive with that of well known insecticides.

One object of this invention is to provide a means for achieving selective, safe, economical control of insect pests.

Another object is to provide chemical compounds that prevent insect maturation when applied topically, injected into, or fed to insects in an immature stage of growth.

A further object of this invention is to provide compounds that adversely affect the biological function of insects, particularly their ability to mature to an adult stage.

A still further object. of the present invention is to provide chemical compounds that will break diapause when applied topically to diapausing adult insects.

In general, according to the present invention the methylenedioxybenzyloxy and methylenedioxyphenoxy ethers of short chain terpenoid derivatives and their corresponding epoxides are synthesized and found to prevent insect maturation when applied topically, injected into or fed to immature stages of several species of insects and to break diapause when applied topically to diapausing adults. Also, when used as a vapor or as a clip for eggs the compounds show considerable potential as fumigants and ovacides.

When an immature insect, that is one in the larval, pupa] or nymphal stage, is treated with these chemicals by contact (topical) or by injection, it is unable to metamorphose into a normal adult. Topical application of as little as 0.1 nanogram (0.0001 microgram) of the more active compounds in this series is sufficient to prevent metamorphosis. The insect which emerges from the treated pupa retains immature genitalia which precludes normal copulation and reproduction. These insects die shortly after molting to this adultoid c0ndition.

The compounds of this invention have the following general formula:

where Y is 0 CH: CH:

CU: (ill: I lI Br l O H Oxidation was accomplished with chromic acid solution in acetone [.l. Chem. Soc. 2548 1953)].

mm n (11.1 n

l l lli llz llal The corresponding vinyl analogs are prepared by the grignard reaction with vinyl magnesium bromide (or chloride) in tetrahydrofuran.

The vinyl analogs were converted to the bromides by treatment with hydrogen bromide in acetic acid. Thus, an aliquot of the vinyl analog was stirred in an ice bath at 5C in an organic solvent such as hexane, benzene, diethyl ether or dichloromethane during the dropwise addition of two molar equivalents of hydrogen bromide as a 30 percent solution in acetic acid. After the addition of HBr the reaction mixture was poured into an ex cess of ice cold 5 percent sodium carbonate, extracted 2 with diethyl ether and washed to neutrality with water. After drying the ethereal extracts over sodium sulfate and removal of the solvent in vacuo the bromide was obtained in nearly quantitative yield.

CH: R

HBr

CH3 R 1-1 mixture of 95 percent ethanol and dimethoxyethane to yield the sesamolyl ethers.

Y The bromides were refluxed with a Sligh molar cess of potassium tert-butoxide and piperonyl alcohol in dimethoxyethane for 3-5 hours to yield the piperochromatography over florisil.

Purity was determined by gas-liquid chromatography and a combination of nuclear magnetic resonance and manner except that the bromides were prepared as'fo llows by a continuation of the Marc Julia synthesis:

The sesamolyl and piperonyl ethers prepared from the bromides had the following several formulas:

in which R is a straight alkyl from one to five carbon atoms such as CH CH CH and CH CH CH etc.

The sesamolyl and piperonyl ethers were epoxidized by stirring them in an organic solvent such as hexane, benzene or methylene chloride during the addition of a slight molar excess of an epoxidizing agent such as mchloro perbenzoic acid. Epoxidation occurred selectively at the terminal double bond within a few minutes to 3 or 4 hours. The reaction mixture was washed with nylethers. 5 percent sodium carbonate and then with water to (13H; l t R---o:o1-IcH,cr{,0- -0Hon, llr. noun, --0

+cm-u 0x (ill:

(111: I li,(!::-()H.Ull10lh(l (mom 0 cm H In all of the reactions above, from the preparation of the terpenoid side chains to the preparation of the sesamolyl and piperonyl ethers, R is astraight chain alkyl from one to five carbon atoms such as CH Ch Cl-l Ch CH Ch etc.

The sesamolyl and piperonyl ethers were purified by neutrality, dried over sodium sulfate and the solvent removed in vacuo. The epoxides were purified by chromatography over florisil.

Purity was ascertained by gas-liquid chromatography and a combination of nuclear magnetic resonance and ultraviolet, infrared and mass spectroscopy to be 99 The sesquiterpenoid side chains of the general formula CH: I III R =CHCHCHC=CHCHCIIC=CHCH- in which iis afii'aight chain alkyl from one to five carbon atoms such as CH CH CH CH CH CH etc. were prepared from the bromides via the acetoacetic ester synthesis. Thus:

R-i:=or1oH,cH@i:=oH 011,131-

1 omii onto 0 0 can o 2 catered onto 0 0 oHi 11 3) CHBCHQOHZC CHZC O 0 CzHs Corresponding keto esters 5 Ro=orromomo=orroHicH-c=oN0H o 00 cm.

which after reflux with 5 percent aqueous sodium hydroxide (l 2 hours) yields the decarboxylated ketone.

CH3 1 I? R-c':=oHomorno=cnomornc=o Reaction of these ketones with vinyl magnesium bromide (or chloride in tetrahydrofuran followed by synthesis of the bromide with hydrogen bromide gave bromides of the following general formula:

R-( 7=cHcnloaio oaomomo oHomer The sesamolyl and piperonyl ethers and their epox- .ides were then prepared as outlined previously for the terpenoid compounds.

Some of the sesamolyl and piperonyl ethers and their epoxides that have been synthesized by the described procedures are listed in Table I.

The morphogenetic effects of some of the compounds in the Tenebrio genitalia assay (Life Sciences 4, 2323-31, 1965) are shown in Table 11. In general, the sesamolyl derivatives were ten times more active than the piperonyl derivatives.

Topical application of 0.01 to 0.1 pg of compound 3. Table l to pupae of Coleoptera such as Tenebrio molitor (yellow mealworm) and Tribolium confusum (confused flour beetle) results in the formation of pupal-adult intermediates. Topical application of 0.001 to 0.1 pg of compounds 7 and produce the same effects. Less dramatic effects such as pupal genitalia are obtained with smaller amounts of these compounds.

Topical application of 1.0 pg of compound 3 and 0.1 pg of compounds 7 and 15 to nymphs of Hemiptera such as Oncopelms fasciatus (milkweed bug) and Pyrrhocoris apterus (red linden bug) caused them to molt to nymphal-adult intermediates with nymphal genitalia and other immature characteristics which prevented them from copulating and reproducing and caused them to die shortly thereafter.

Topical treatment of Diptera prepupae and pupae such as Musca domestica (housefly) with 0.5 to 1.0 pg of compound 3 caused development of pupal-adult intermediates which died within the puparium.

Adult emergence of another Diptera, Aedes aegypti (yellow fever mosquito) was completely inhibited by exposure of fourth instar mosquito larvae to 0.1 parts per million of compound 3 in water. Pupation of this insect was completely inhibited by exposure of the larvae to 1.0 to 10.0 parts per million of compound 3.

' Topical application of l 0 to 100 pg of compounds 3, 7 and 15 to larvae of Lepidoptera such as Manduca sexta (tobacco hornworm) caused prolongation of molting cycle and feeding period, extra larval molts, failure to pupate and death. Feeding the larvae the same compounds at a dosage level of 0.01 to 125.0 parts per million caused the same effects. Similar results were obtained when larvae of Heliothis zea (corn earworm) were treated with these compounds.

When pupae of Manduca sexta were treated topically or injected with 1.0 to 5.0 pg of the compounds of this invention they molted to pupal-adult intermediates or second pupae which were unable to reproduce and died shortly thereafter.

Although the vapor pressures of the compounds of this invention are not very high, the compounds are so active that when Tenebrio molitor and Tribolium confusum pupae were confined in pint jars containing as little as 100 pg of compounds 3, 7 and 15 per jar they molted to second pupae and pupal-adult intermediates and died shortly thereafter. The pupae were suspended in the jar in such a manner that they did not contact the compounds directly but were simply exposed to the vapor. These results exemplify the potential use of the compounds of this invention as fumigants.

When eggs of the Epilachna varivestis (Mexican bean beetle) were dipped into a solution containing 10 parts per million of compound 3, they failed to undergo embryogenesis and none of the eggs hatched. This exemplifies the potential use of these compounds as ovacides.

Incorporating these compounds in the diets of insects affected the insects in several ways depending on the dosage. The diet studies were confined mostly to Tribolium confusum because it has a short larval cycle and can be handled with ease. Tribolium larvae fed a diet containing 0.1 to 10.0 parts per million of compounds 3, 7 and 15 underwent supemumerary molting to larger and larger larvae until they became two to two and one-half times normal size. The larval life cycle was extended from the normal 20 days to or more days, food consumption was increased two to three times and the larvae eventually died without developing to the adult stage.

Although feeding may not appear to be useful in con- Ulla I CH3 H7 31 (1H 60 39 CH; (1311:

(311a lCH2 a CH3 CH2 OH:

40 n. (iii (|1T3 (tin vii, (ii1oii,( -:oiiuiimi tll 'tllmt IHHQ o (I11 Table II plished by topical application, injection, feeding, Morphogenetiacmem of lo exposing to vapors of the compound or dipping in Representative compounds in solutions of the compound. the Tencbrio Genitalia Assay 2. The method of claim 1 in which Y is Compound Micrograms of Compound Required to Produce the Indicated Morphogenetic Effects H Number Pupal Adult R C"CH in intermediates Pupal Genitalia' 'llablel l 0 0 1 3. The method of claim 2 in which R and R" are 2 10.0 110 methyl and x is 1. I g 8-3 886 4. The method of claim 2 in which R is methyl, R" is 7 0'00! ()0005 ethyl andx is 1. 9 0:005 5. The method of claim 2 in which R is methyl, R is 11 0.001 0.0005 ethyl and x is 2. :2 828 8333 6. The method of claim 2 in which R and R" are 17 10.0 1.0 ethyl and x is 1. 18 10.0 100.0 9 L0 OJ 7. The method of claim 1 in which Y is 20 10.0 1.0

' Pupal adult intermediates CH1 represent an intermediate in which the insect molts to a R" 'C*""CH monster with an essentially pupal 0 abdomen and adultoid head and thorax. Pupal genitalia refers to the 8. The method of claim 7 in which R is methyl, R" is effect in which the insect is th I and x is 2 nearly adult but with immature e y H Egetiliingltila. b h 9. The method of claim 7 in which R is ethyl, R [8 ac o e a ove morp ogenetic effects causes the insect to die methyl and x IS 1 I I Shortly thereafter. 10. The method of claim 7 in which R and R are methyl and x is 2. Iclalm! 11. The method of claim 7 in which R is ethyl, R is l. A method of controlling insects selected from the h l d x i '2 group consisting of Tenebrio molitor (L.), Tribolium 12 The method f claim 7 i hi h R d R" are confusum (Duval), Pyrrhocoris apterus (L.), Oncopeltus 40 ethyl and x is fasciatus (Dallas), Manduca sexta, Musca domestica. The method f l i 1 in whichy is Aedes aegyptz, Heliothis zea and Epilachna varivestis which comprises contacting said insects at an immature stage of growth with an effective maturation inhibiting 3=CH(CH=)2 amount of a compound of the formula: v

i R 14. The method of claim 13 in which R, R, and R" l are methyl Y(CH) C=CH(CH ).0- 0Ii )n 0 2 2 2 2 15. The method of claim 14 in which n is 0. 0 16. The method of claim 14 in which n is l. 17. The method of claim 14 in which x is 1. where Y is selected from the group consisting of The method of clam] 1 m whlch Y (EH3 OH: 1? RCCH R" rJ 0H(CHi)=C= 1 on. H. 1? "-CC h): 19. The method of claim 18 is which'R, R and R" o are methyl. and 20. The method of claim 19 in which n is 0. CH; R 21. The method of claim 19 in which n is l.

n is a number from 0 to 3;

x is a number from 1 t0 2;

and R, R and R" are straight chain alkyls from one to five carbon atoms, said contacting being accom- 22. The method of claim 19 in which x is 1.

23. The method of claim 18 in which R and R are methyl, R" is ethyl and x is 1.

24. The method of claim 18 in which R and R" are methyl, R is ethyl and x is 1.

25. The method of claim 18 in which R is ethyl, R and R" are methyl and x is 1.

26. The method of claim 18 in which R, R and R" are ethyl and x is 1.

27. A method of controlling insects selected from the group consisting of Tenebrio molitor (L.), Tribolium confusum (Duval), Pyrrhocoris apterus (L.), Oncopeltus fascr'ams (Dallas), Manduca sexta, Musca domestica, Aedes aegypti, Heliothis zea and Epilachna varivestis which comprises contacting said insects at an immature stage of growth with an effective maturation inhibiting amount of 3', 4'-methylenedioxyphenoxy-6,7-epoxy, 3, 7-dimethyl-2-octene, said contacting being accomplished by topical application, injection, feeding, exposing to vapors of the compound or dipping in solutions of the compound.

28. A method of controlling insects selected from the group consisting of Tenebrio molitor (L), Tribolium confusum (Duval), Pyrrhocaris apterus (L), Oncopeltus fascictus (Dallas), Manduca sexta, Musca domestica, Aedes aegypti, Heliothis zea and Epilachna varivestis which comprises contacting said insects at an immature stage of growth with an effective maturation inhibiting amount of 3', 4-methylenedioxyphenoxy-6,7-epoxy, 3,7-dimethyl-2-nonene, said contacting being accomplished by topical application, injection, feeding, exposing to vapors of the compound or dipping in solutions of the compound.

29. A method of controlling insects selected from the group consisting of Tenebrio molitor (L.), Tribolium confusum (Duval), Pyrrhocoris apterus (L), Oncopeltus fasciatus (Dallas), Manduca sexta, Musca domestica, Aedes aegypti, Heliothis zea and Epilachna varivestis which comprises contacting said insects at an immature stage of growth with an effective maturation inhibiting amount of 3, 4-methylenedioxyphenoxy-6,7-epoxy, 3ethyl, 7-methyl-2-nonene, said contacting being accomplished by topical application, injection, feeding, exposing to vapors of the compound or dipping in solutions of the compound. 

2. The method of claim 1 in which Y is
 3. The method of claim 2 in which R and R'''' are methyl and x is
 4. The method of claim 2 in which R is methyl, R'''' is ethyl and x is
 1. 5. The method of claim 2 in which R is methyl, R'''' is ethyl and x is
 2. 6. The method of claim 2 in which R and R'''' are ethyl and x is
 7. The method of claim 1 in which Y is
 8. The method of claim 7 in which R is methyl, R'''' is ethyl and x is
 2. 9. The method of claim 7 in which R is ethyl, R'''' is methyl and x is
 1. 10. The method of claim 7 in which R and R'''' are methyl and x is
 2. 11. The method of claim 7 in which R is ethyl, R'''' is methyl and x is
 2. 12. The method of claim 7 in which R and R'''' are ethyl and x is
 2. 13. The method of claim 1 in which Y is
 14. The method of claim 13 in which R, R'', and R'''' are methyl.
 15. The method of claim 14 in which n is
 0. 16. The method of claim 14 in which n is
 1. 17. The method of claim 14 in which x is
 1. 18. The method of claim 1 in which Y is
 19. The method of claim 18 is which R, R'' and R'''' are methyl.
 20. The method of claim 19 in which n is
 0. 21. The method of claim 19 in which n is
 1. 22. The method of claim 19 in which x is
 1. 23. The method of claim 18 in which R and R'' are methyl, R'''' is ethyl and x is
 1. 24. The method of claim 18 in which R and R'''' are methyl, R'' is ethyl and x is
 1. 25. The method of claim 18 in which R is ethyl, R'' and R'''' are methyl and x is
 1. 26. The method of claim 18 in which R, R'' and R'''' are ethyl and x is
 1. 27. A method of controlling insects selected from the group consisting of Tenebrio molitor (L.), Tribolium confusum (Duval), Pyrrhocoris apterus (L.), Oncopeltus fasciatus (Dallas), Manduca sexta, Musca domestica, Aedes aegypti, Heliothis zea and Epilachna varivestis which comprises contacting said insects at an immature stage of growth with an effective maturation inhibiting amount of 3'', 4''-methylenedioxyphenoxy-6,7-epoxy, 3, 7-dimethyl-2-octene, said contacting being accomplished by topical application, injection, feeding, exposing to vapors of the compound or dipping in solutions of the compound.
 28. A method of controlling insects selected from the group consisting of Tenebrio molitor (L.), Tribolium confusum (Duval), Pyrrhocoris apterus (L.), Oncopeltus fasciatus (Dallas), Manduca sexta, Musca domestica, Aedes aegypti, Heliothis zea and Epilachna varivestis which comprises contacting said insects at an immature stage of growth with an effective maturation inhibiting amount of 3'', 4''-methylenedioxyphenoxy-6,7-epoxy, 3,7-dimethyl-2-nonene, said contacting being accomplished by topical application, injection, feeding, exposing to vapors of the compound or dipping in solutions of the compound.
 29. A method of controlling inseCts selected from the group consisting of Tenebrio molitor (L.), Tribolium confusum (Duval), Pyrrhocoris apterus (L.), Oncopeltus fasciatus (Dallas), Manduca sexta, Musca domestica, Aedes aegypti, Heliothis zea and Epilachna varivestis which comprises contacting said insects at an immature stage of growth with an effective maturation inhibiting amount of 3'', 4''-methylenedioxyphenoxy-6,7-epoxy, 3ethyl, 7-methyl-2-nonene, said contacting being accomplished by topical application, injection, feeding, exposing to vapors of the compound or dipping in solutions of the compound. 